A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (COMBO)

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The study consists of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase will evaluate the safety, tolerability, and PK of avelumab in combination with NHS-IL12 in subjects with locally advanced, unresectable, or metastatic solid tumors. Expansion phase will assess the safety and clinical activity of the combination regimen in selected tumor types. In Expansion phase subjects who have completed the combination treatment of avelumab at a given dose level of NHS-IL12, a safety review will be performed by the Safety monitoring committee in order to make a decision on the next dose level. Successive cohorts of 3 to 6 subjects will be treated with escalating doses of NHS-IL12 with avelumab intravenous (IV).

A Phase Ib Open‑Label, Dose‑Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination With M9241(NHS-IL12) in Subjects With Locally Advanced, Unresectable, or Metastatic Solid Tumors

Part A and B: Occurrence and Severity of Treatment Emergent Adverse Events (TEAEs) and related TEAEs [ Time Frame: Up to 124 Weeks ]

Part A: Number of Subjects With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 3 weeks ]

Part A: Duration of TEAEs and Related TEAEs [ Time Frame: Up to 52 weeks ]

Part B: Best Overall Response (BOR) by Investigator Assessment [ Time Frame: Up to 124 weeks ]

Secondary Outcome Measures
:

Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab [ Time Frame: Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion ]

Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of Avelumab [ Time Frame: Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion ]

Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of NHS-IL12 [ Time Frame: Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion ]

Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of NHS-IL12 [ Time Frame: Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion ]

Part B: Duration of Response According to RECIST v1.1 Criteria Assessed by Investigator [ Time Frame: Baseline until 124 weeks ]

Part B: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab and NHS-IL12 [ Time Frame: Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) ]

Part B: Area Under the Concentration Time Curve From Time of Dosing to Infinity (AUC0-inf) of Avelumab and NHS-IL12 [ Time Frame: Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) ]

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Part A:

Subjects must have signed written informed consent.

Male or female subjects age greater than equals to (>=)18 years.

Subjects must have histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists, standard therapy has failed, or subject is intolerant of established therapy known to provide clinical benefit for their condition.

Subjects who have been treated previously with a checkpoint inhibitor may enroll (except as outlined below for expansion cohorts).

At least 1 unidimensional radiographically measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), except for subjects with metastatic castration-resistant prostate cancer (CRPC) or metastatic breast cancer who may be enrolled with objective evidence of disease without a measureable lesion.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at Screening

Estimated life expectancy of more than 12 weeks

Adequate hematological function as defined below:

White blood cells (WBC) count >= 3.0 × 10^9 per liter (/L)

Absolute neutrophil count >= 1.5 × 10^9/L

Lymphocyte count >= 0.5 × 10^9/L

Platelet count >= 100 × 10^9/L

Hemoglobin >= 9 gram per deciliter (g/dL) (may have been transfused)

Adequate hepatic function as defined below:

A total bilirubin level lass than equals to (<=) 1.5 × the upper limit of normal (ULN) range

Aspartate aminotransferase (AST) levels <= 2.5 × ULN

Alanine aminotransferase (ALT) levels <= 2.5 × ULN

Subjects with documented Gilbert disease are allowed if total bilirubin > 1.5 but less than 3 × ULN

Adequate renal function as defined by an estimated creatinine clearance >= 50 milliliter per minute (mL/min) according to the Cockcroft-Gault formula

Negative blood pregnancy test at Screening for women of childbearing potential. For the purposes of this trial, women of childbearing potential are defined as all female subjects after puberty unless they are postmenopausal for at least 1 year, are surgically sterile or are sexually inactive.

Highly effective contraception (ie, methods with a failure rate of less than 1% per year) must be used before the start of treatment, for the duration of the trial treatment, and for at least 50 days after stopping study treatment for both men and women if the risk of conception exists. The effects of avelumab and NHS-IL12 on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception.

Part B:

Urothelial carcinoma (UC) post-platinum: Histologically or cytologically confirmed locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Subjects must have progressed after treatment with at least 1 platinum containing regimen for inoperable locally advanced or metastatic UC or disease recurrence. Availability of either tumor archival material or fresh biopsies within 28 days is acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment.

Non-small cell lung cancer (NSCLC), first-line metastatic: Stage IV (per seventh International Association for the Study of Lung Cancer classification) histologically confirmed NSCLC. Subjects must not have received treatment for their metastatic disease. Subjects could have received adjuvant chemotherapy or loco-regional treatment that included chemotherapy for locally advanced disease, as long as disease recurrence occurred at least 6 months after the completion of the last administration of chemotherapy. Only epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type are allowed (ie, EGFR mutation and ALK translocation / re arrangement excluded). Non squamous cell histologies and never / former light smoker (< 15 pack years) squamous cell carcinoma subjects (per local standard of care) require testing if status is unknown. Subjects must have low tumor PD-L1 expression defined as < 50% tumor proportion score determined using PD-L1 IHC 22C3 pharmDx test or an equivalent Food and Drug Administration (FDA)- approved PD-L1 test. This cohort will not be opened for enrollment in Belgium, Czech Republic, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom. Availability of either tumor archival material or fresh biopsies within 28 days is acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment.

Colorectal cancer (CRC): Histologically or cytologically confirmed recurrent or refractory metastatic CRC (according to American Joint Committee on Cancer / International Union Against Cancer Tumor Node Metastasis [TNM] Staging System seventh edition) after failure of prior therapy containing oxaliplatin / fluoropyrimidine and / or irinotecan / fluoropyrimidine and, if eligible, cetuximab (Erbitux®) and bevacizumab (Avastin®). Only subjects with microsatellite instability (MSI)-low or microsatellite stable (MSS) metastatic CRC are eligible. Subjects without existing MSI test results will have MSI status performed locally by a Clinical Laboratory Improvement Amendments (CLIA)-certified IHC or polymerase chain reaction (PCR)-based test (PCR based MSI test is preferred). Subjects must be willing to undergo an on-treatment biopsy procedure. For Belgium, Czech Republic, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, subjects in the second-line setting should have exhausted or be considered ineligible or intolerant (in the opinion of the Investigator) of available second-line chemotherapy options. Availability of either tumor archival material or fresh biopsies within 28 days is acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment.

Renal cell carcinoma (RCC), primary immune checkpoint inhibitor failure: Histologically or cytologically documented metastatic RCC with a component of clear cell subtype. Subjects must have had progressive disease (PD) within 6 months or best overall response of stable disease (SD) for ≥ 6 months following start of therapy with any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) for advanced or metastatic disease (either as monotherapy or combination therapy, in any line). Availability of a fresh tumor biopsy is mandatory for eligibility in the RCC cohort. The biopsy or surgical specimen should be collected within 28 days prior to the first IMP administration. Subjects must also be willing to undergo an on-treatment biopsy procedure.

Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to start of trial treatment, or not recovered from adverse event (AE) related to such therapies, with the following exceptions: Palliative radiotherapy delivered in a normal organ-sparing technique is permitted; Erythropoietin and darbepoetin-α are permitted; Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (i.e. luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is permitted.

Major surgery (as deemed by Investigator) for any reason, except diagnostic biopsy, within 4 weeks prior to start of trial treatment, or not fully recovered from surgery within 4 weeks prior to start of trial treatment

Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before start of trial treatment, with the following exceptions: Subjects with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to less than (<) 10 mg prednisone daily; Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is permitted; Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the dose after 14 days will be equivalent to <= 10 mg prednisone daily.

Previous malignant disease (other than the indication for this trial) within the last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to trial entry and the subject was deemed to have been cured with no additional therapy required or anticipated to be required.

Active tuberculosis (history of exposure or history of positive TB (tuberculosis) test with presence of clinical symptoms, physical, or radiographic finding

Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible if they are stable on other medical treatment and do not fulfill exclusion criterion including Uncontrolled intercurrent illness

History of allergic reaction to methotrexate (trace methotrexate may be present in NHS-IL12 as a part of the manufacturing process) or history of severe hypersensitivity reaction to any other ingredient of the study drug(s) and / or their excipients. Since NHS-IL12 contains sucrose as an excipient, subjects suffering from hereditary fructose intolerance are also excluded

Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.03 with the following exceptions:

All other significant diseases (eg, inflammatory bowel disease, current severe acute or chronic colitis) or chronic medical conditions (including laboratory abnormalities) that in the opinion of the Investigator might impair the subject's tolerance of trial treatment or interpretation of trial results.

Any psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with trial requirements.

Legal incapacity or limited legal capacity.

Administration of a live vaccine within 30 days prior to trial entry.

Any subject with possible area of ongoing necrosis (non-disease related), such as active ulcer, non-healing wound, or intercurrent bone fracture that may be at risk of delayed healing due to protocol therapy.